EP0186360B1 - Verfahren zur Herstellung von hochgereinigten, Hepatitis-B-Virus-infektionsfreien Gammaglobulinen - Google Patents
Verfahren zur Herstellung von hochgereinigten, Hepatitis-B-Virus-infektionsfreien Gammaglobulinen Download PDFInfo
- Publication number
- EP0186360B1 EP0186360B1 EP85308922A EP85308922A EP0186360B1 EP 0186360 B1 EP0186360 B1 EP 0186360B1 EP 85308922 A EP85308922 A EP 85308922A EP 85308922 A EP85308922 A EP 85308922A EP 0186360 B1 EP0186360 B1 EP 0186360B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- buffer
- column means
- resin
- sephadex
- column
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
- C07K16/065—Purification, fragmentation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to a process for the preparation of highly purified gamma globulins free of hepatitis-B-virus infectivity.
- gamma globulin Numerous medical conditions require treatment via injection of gamma globulin.
- the manner of preparation of the gamma globulin is of critical importance, particularly in order to eliminate the chance of contracting viral hepatitis.
- Viral hepatitis is a debilitating disease at best and lethal at worst. Consequently, any advances made to eliminate the chance of contamination of any injectable product by this virus are of immense importance.
- Hepatitis B virus is estimated to infect approximately 200 million persons worldwide. Since the base material for the production of gamma globulins often is plasma obtained from a human source, the chances of obtaining contaminated or infected plasma are significant in view of the substantial number of persons who are chronically and acutely infected.
- the infected plasma from such a person may contain not only varying amounts of viral particles but also different sizes and forms of the particles. The most common form is the spherical particle which has a mean diameter of 22 nm. These spherical particles are devoid of DNA and represent free envelopes of the virus.
- the 42 nm Dane particles which represent the virion and consist of an envelope and a 27 nm nucleocapsid that contains a molecule of DNA. Free nucleocapsids may be observed in the nucleus of infected hepatocytes but are generally not found in the plasma. Infected hepatocytes have been found to synthesize excessive amounts of envelope which can be found circulating throughout the body.
- different immunological markers have been identified. For example, associated with the core is an antigen commonly labelled HB c Ag and an "e" antigen labelled HB e Ag.
- Ths most common antigen employed for the detection of hepatitis B virus infection is the surface antigen HB s Ag.
- the structure and genetic organization of the hepatitis viral particle has been reviewed in an article by Tiollais et al., in Biology of Hepatitis B Virus, Science, Vol. 213, 406 ⁇ 411 (July, 1981). Further discussion concerning the association of the Australian antigen with persistent or chronic hepatitis may be obtained in Australia Antigen and Hepatitis by Blumberg et al., C.R.C. Monotopic Series, C.R.C. Press, Cleve- land, Ohio (1982). The close relationship of hepatitis B surface antigen to hepatitis viral infectivity is discussed by Blumberg, supra, on page 14.
- the resulting gamma globulin product would also be safe for both intramuscular or intravenous injections.
- Condie has described in U.S. Patent No. 4,136,094, "Preparation of Intravenous Human and Animal Gamma Globulins and Isolation of Albumin", another method for obtaining gamma globulin which is claimed safe for intravenous administration.
- Condie's method involves three manipulations including plasma stabilization by treatment with fumed colloidal silica, isolation and elution of gamma globuin and albumin from the exchange resins and finally concentration dialysis and sterile filtration.
- the fumed colloidal silica step is provided to remove hepatitis associated antigen present in the plasma as well as a number of proteolytic enzymes and their precursors.
- the colloidal silica treated materials were tested for presence of hepatitis associated antigen by radioimmunoassay.
- testing by presently available radioimmunoassay procedures will not ensure that the tested sample is free of infective hepatitis. Without further testing, any such material will not be approved by the U.S. government for widespread use in excess of that required for limited clinical studies.
- Rho Rho
- RhoGAMO available from the assignee hereof, operates by preventing the unimmunized Rho (D) negative mother from responding to Rho (D) antigen present on red cells and "received" at delivery from an Rho (D) positive infant.
- Hoppe's source of anti-D containing plasma was from volunteers who passed an HB s Ag laboratory test for at least six months, the plasma being stored in the interim. Thus, Hoppe employed a relatively safe, noninfective plasma to start with. Some screening work was done in Hoppe's laboratory to confirm the affinity of HB s AG for these resins. To our knowledge, no animal safety work was done to confirm removal of infectivity.
- Hoppe's concern was directed towards the removal of aggregated materails and the isolation of an unfragmented, immunoelectrophoretically pure IgG having a relatively high antibody concentration.
- the Friesen publication reports on the modifications made to the Hoppe method for the development of an intravenous Rh IgG for use in Canada. As Hoppe had done, Friesen tested each unit of Rh plasma for HB S AG to eliminate any donors testing positive. Friesen employed the radioimmuonoassay kit from Abbott Laboratories, North Chicago, Illinois (Austria II Kit). This test is still regarded as one of the most sensitive and was also employed in the development of the invention described later.
- the ratio of A-50 resin per ml of applied sample was required to be no lower than 160 mg/ml to insure adequate removal of surface antigen.
- the resin used is extremely expensive and this is compounded by the fact that, for safety reasons, such resin should preferably be virgin and discarded after each trial.
- hepatitis B virus infectivity from a gamma globulin containing body fluid that has most preferably been properly screened by third generation HB s Ag tests.
- body fluid is most preferably adjusted by dialysis or dilution to match the running conditions (pH and conductivity) of the subsequent columns.
- the removal of the antigens is effectuated by the application of the body fluid to first and second columns in series.
- the first column contains an effective amount of a rigid resin consisting of DEAE-Sepharose CL-6B ® , DEAE-Sepharose CL-6B @ (Fast Flow), DEAE-Spherodex @ or DEAE Bio-Gel® (High Capacity) and said second column contains an effective amount of a nonrigid resin consisting of DEAE-Sephadex @ or QAE-Sephadex O .
- the body fluid is then eluted form the first column means with a buffer adjusted to a pH of at least 7.0, said buffer consisting of approximately 0.02 M phosphate buffer, if the resin selected for said second column means is QAE-Sephadex®, or said buffer consisting of approximately 0.04 M Tris buffer, approximately 0.05 M imidazole buffer, or approximately 0.035 M sodium phosphate [Na 2 HP0 41 -citric acid buffer, if the resin selected for said second column means is DEAE-Sephadex® or QAE-Sephadex ® .
- the effluent from the first column is monitored for the presence of protein (preferably by optical measurement at 280 nm), those fractions containing protein being collected and pooled.
- This pooled protein is applied to the second column, the fluid from the second column being eluted with one of the buffers which may be utilized in said first column, the buffer being adjusted to a pH of at least 7.0.
- the second column effluent is then preferably monitored for the presence of protein. Thereafter, the effluent is collected responsive to protein monitoring whereby purified gamma globulin free of hepatitis-B virus infectivity is obtained.
- the diluted purified gamma globulin product in this effluent is then preferably concentrated by standard methods, for example, ultrafiltration, to produce a finished product.
- the effective amount of A-50 resin in said second column is an amount at least equal to 100 mg/ml of body fluid.
- the effective amount of resin comprises a mixture of at least 27-1/2 mg of A-25 type resin per ml of body fluid for every 80 mg of A-50 type resin per ml of body fluid.
- the resin used in the second column comprises a mixture of 55 mg of QAE Sephadex® type A-25 and 100 mg of QAE Sephadex® type A-50 per ml of body fluid.
- a preferred combination is one in which the resin in the first column is DEAE-Sepharose CL-6B O and the buffer is approximately 0.05 M imidazole buffer; and the resin in the second column is QAE-Sephadex®, the buffer used being approximately 0.05 M imidazole buffer.
- the buffer utilized in each column is preferably adjusted to a pH of between 7.25 and 8.0, and most preferably to a pH of approximately 7.5.
- the present invention utilizes a double- column system, rather than the single-column system shown in U.S. Patent No. 4,434,093.
- a similar ion exchange resin/ buffer system is used in the second column.
- a first column through which the plamsa is passed.
- the first column contains a rigid resin which removes about 75% of plasma proteins such as albumin.
- This resin has excellent flow characteristics and can be used in large-scale column operations.
- this rigid resin can be regenerated many times (from 20 to 50 times) without loss of binding efficiency.
- the rigid resin is inadequate for the complete removal of HB s Ag, since some of the interfering proteins may be removed in the first column, the present invention enables the amount of A-50 resin in the second column to be reduced from 160 to 100 milligrams per ml of undiluted plasma, yet still providing adequate binding of the virus.
- the present system provides scale-up advantages and greater economy as compared to that of the Zolton et al. U.S. Patent No. 4,434,093.
- albumin is removed in the first column as well as most of the other proteins, in accordance with the present process.
- the removal of the hepatitis-B-virus in the second column has been found to be much more efficient so that the effective amount of A-50 resin needed in the second column may be reduced, as stated above, to 100 mg/ml of body fluid.
- the present invention provides an improved system which utilizes two columns, the first column containing a rigid resin which has excellent scale-up properties which has been shown to be capable of being regenerated and reused mutliple times.
- This rigid resin is used to remove the bulk of the protein such as albumin, although it is not used to remove a large amount of the hepatitis virus.
- the product from the first column when passed over the second column containing a lower amount of soft resin (as compared to that used in the Zolton et al. U.S. Patent No. 4,434,093), has a high ability to remove any virus which escaped from the first column.
- the resin in the second column should preferably be virgin and discarded after each trial.
- the pH and conductivity ranges specified in the Zolton et al, prior U.S. Patent No. 4,434,093 have not been changed for the purposes of the present invention, with respect to the actual trials conducted.
- HBV infected inoculum (HB s Ag subtype adr) was obtained from the United States Bureau of Biologics of the food and Drug Administration. Starting infectivity was 10 5 l.D./ml and the product was stabilized in calf serum and stored in the frozen state. Fresh human plasma was collected from each of 3 normal females and males and tested individually for Hb s Ag, anti-HB c and anti-HB s by RIA procedures. All six samples were found to be negative and the samples were pooled and then stored frozen. At the time of the trial both the inoculum and the normal plasma pool were thawed. The cold insolubles were removed from the latter by a standard centrifugation method.
- DEAE-Sepharose CL-6B 5 and QAE-Sephadex ® A-25 and A-50 were purchased from Pharmacia Fine Chemicals.
- the buffer used was a 0.05M imidazole-0.02M sodium chloride.
- the pH was 7.5 ⁇ 0.1 and the conductivity was 2.2 ⁇ 0.4 millisiemens (5°C). All reagents were of reagent grade and the source of each was Sigma (imidazole) and J. T. Baker (Sodium Chloride).
- the sample (designated B) scheduled for treatment was prepared as described above in the Pre-Treatment Procedure. Volume after pre-treatment was 10 ml and HBV infectivity was 5000 l.D./ml. The level of viral contamination was deliberately chosen so that at the point of application to column one, the sample would be weakly positive when tested by a third generation RIA procedure for HB s Ag. The trial, therefore represented an extreme challenge since this or higher levels of virus should not be encountered by a manufacturer who tests all in-coming units of blood. Prior to sample application, both columns were paced with appropriate swollen resin.
- the amount of DEAE-Sepharose CL-6B @ in column one was at a ratio of one volume of resin (0.15 m Equiv.) for each volume of the initial plasma-virus mix. This resin had been exposed previously to three different loadings of uncontaminated diluted plasma and regenerated after each loading per the manufacturer's procedure.
- column two a mixture of virgin QAE-Sephadex ® resins A-25 and A-50 type were packed at a weight ratio of 55 mg of A-25 dry resin and 100 mg A-50 dry resin for each ml of the initial plasma-virus mix.
- the resin beds in both columns were flushed with buffer to establish a baseline OD 28o nm reading.
- the diluted plasma-virus mix was applied to column one at a flow rate of 105-115 cm/HR.
- the product volume was approximately twice its applied volume. This product was applied directly to column two and the same elution procedure was followed except the flow rate for this non-rigid resin was 50-55 cm/HR. The highly purified IgG product from this column experienced a 1.5 times increase in volume from application to column two.
- the untreated sample was diluted with a pH 7.5 buffer comprised of 0.05M Imidazole-0.154M sodium chloride-1.0% human albumin. Separately, this buffer was shown to be free of any hepatitis markers. After dilution, the untreated sample had an infectivity level of 20 l.D./ml.
- the treated sample was diluted likewise so its final pH, conductivity and protein concentration would be similar to that of the untreated sample. After dilution, the infectivity level of the treated sample could be 1300 l.D./ml assuming no virus removal by the two column system.
- the control animal received 5.0 ml intravenously of the diluted untreated sample for a challenge of 100 l.D.
- Each of the experimental animals received 2.3 ml intravenously of the diluted treated sample for a protential challenge of 3000 I.D. None of the animals had any adverse effects to their intravenous injection.
- ALT alanine aminotransferase
- ALT levels were elevated from weeks 27 to 29 inclusive with a peak value of 265 IU/L. Further confirmation of the disease was obtained from the analysis of the needle biospies (week 30).
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Claims (10)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT85308922T ATE55257T1 (de) | 1984-12-10 | 1985-12-09 | Verfahren zur herstellung von hochgereinigten, hepatitis-b-virus-infektionsfreien gammaglobulinen. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US68019184A | 1984-12-10 | 1984-12-10 | |
US680191 | 1984-12-10 | ||
US735013 | 1985-05-17 | ||
US06/735,013 US4590002A (en) | 1984-12-10 | 1985-05-17 | Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0186360A2 EP0186360A2 (de) | 1986-07-02 |
EP0186360A3 EP0186360A3 (en) | 1986-12-03 |
EP0186360B1 true EP0186360B1 (de) | 1990-08-08 |
Family
ID=27102408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP85308922A Expired - Lifetime EP0186360B1 (de) | 1984-12-10 | 1985-12-09 | Verfahren zur Herstellung von hochgereinigten, Hepatitis-B-Virus-infektionsfreien Gammaglobulinen |
Country Status (7)
Country | Link |
---|---|
US (1) | US4590002A (de) |
EP (1) | EP0186360B1 (de) |
JP (1) | JPH0764753B2 (de) |
AU (1) | AU579434B2 (de) |
CA (1) | CA1272131A (de) |
DE (1) | DE3579136D1 (de) |
MX (1) | MX166053B (de) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0669961B2 (ja) * | 1984-09-25 | 1994-09-07 | 株式会社ミドリ十字 | 免疫グロブリンの加熱処理方法 |
US4590002A (en) * | 1984-12-10 | 1986-05-20 | Ortho Diagnostic Systems, Inc. | Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity |
US4606825A (en) * | 1985-04-22 | 1986-08-19 | J. T. Baker Chemical Company | Purification of immunoglobulin G |
NZ216094A (en) * | 1985-05-15 | 1989-06-28 | Commw Serum Lab Commission | Method for purification of an immunoglobulin |
DE3640513A1 (de) * | 1986-11-27 | 1988-06-09 | Biotest Pharma Gmbh | Verfahren zur herstellung eines virussicheren, lagerstabilen und intravenoes vertraeglichen immunglobulin-g-praeparates |
US5219578A (en) * | 1991-02-25 | 1993-06-15 | Innovet, Inc. | Composition and method for immunostimulation in mammals |
AT407159B (de) * | 1997-06-13 | 2001-01-25 | Immuno Ag | Verfahren zur abreicherung von viralen und molekularen pathogenen aus einem biologischen material |
US6096872A (en) * | 1997-10-14 | 2000-08-01 | Ortho Diagnostic Systems, Inc. | Viral clearance process |
GB0015913D0 (en) | 2000-06-30 | 2000-08-23 | Johnson Electric Sa | Star connected rotor |
AU784808B2 (en) * | 2001-04-02 | 2006-06-29 | Kedrion Melville Inc. | Prion and viral clearance process |
WO2002094407A2 (en) * | 2001-05-22 | 2002-11-28 | University Of Vermont And State Agricultural College | Protein fractionation and single p0lymer matrix unit chromatography |
US7172739B2 (en) | 2001-05-22 | 2007-02-06 | University Of Vermont And State Agricultural College | Protein fractionation |
US7201901B2 (en) * | 2002-05-23 | 2007-04-10 | Ortho-Clinical Diagnostics, Inc. | Capture, concentration and quantitation of abnormal prion protein from biological fluids using depth filtration |
AU2005229674B2 (en) * | 2004-11-18 | 2010-11-04 | Kedrion Melville Inc. | Low concentration solvent/detergent process of immuneglobulin with pre-treatment |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK139056B (da) * | 1976-04-06 | 1978-12-11 | Nordisk Insulinlab | Fremgangsmåde til udvinding af immunoglobulin, der er egnet til intravenøs indgivelse. |
US4136094A (en) * | 1977-08-31 | 1979-01-23 | The Regents Of The University Of Minnesota | Preparation of intravenous human and animal gamma globulins and isolation of albumin |
US4162192A (en) * | 1978-09-28 | 1979-07-24 | Juridical Foundation | Method for purification of HBs antigen |
JPS5598117A (en) * | 1979-01-17 | 1980-07-25 | Chemo Sero Therapeut Res Inst | Purification of gamma-globulin derivative |
US4272521A (en) * | 1979-07-16 | 1981-06-09 | Cutter Laboratories, Inc. | Purified immune serum globulin |
CA1168152A (en) * | 1981-10-20 | 1984-05-29 | Winnipeg Rh Institute Inc. (The) | Process for preparing human plasma fractions containing immune globulin (igg) |
US4434093A (en) * | 1982-07-26 | 1984-02-28 | Ortho Diagnostic Systems Inc. | Methods for preparation of HBs Ag free gamma globulins |
DE3310150A1 (de) * | 1983-03-21 | 1984-09-27 | Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München | Verfahren zur herstellung einer nebenwirkungsfreien igg-immunglobulinloesung fuer die intravenoese applikation |
US4590002A (en) * | 1984-12-10 | 1986-05-20 | Ortho Diagnostic Systems, Inc. | Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity |
-
1985
- 1985-05-17 US US06/735,013 patent/US4590002A/en not_active Expired - Lifetime
- 1985-12-06 CA CA000497077A patent/CA1272131A/en not_active Expired - Lifetime
- 1985-12-09 AU AU51030/85A patent/AU579434B2/en not_active Expired
- 1985-12-09 EP EP85308922A patent/EP0186360B1/de not_active Expired - Lifetime
- 1985-12-09 DE DE8585308922T patent/DE3579136D1/de not_active Expired - Lifetime
- 1985-12-10 JP JP60276162A patent/JPH0764753B2/ja not_active Expired - Fee Related
- 1985-12-10 MX MX026449A patent/MX166053B/es unknown
Also Published As
Publication number | Publication date |
---|---|
JPS61145125A (ja) | 1986-07-02 |
AU5103085A (en) | 1986-06-19 |
US4590002A (en) | 1986-05-20 |
JPH0764753B2 (ja) | 1995-07-12 |
DE3579136D1 (de) | 1990-09-13 |
MX166053B (es) | 1992-12-16 |
CA1272131A (en) | 1990-07-31 |
EP0186360A3 (en) | 1986-12-03 |
EP0186360A2 (de) | 1986-07-02 |
AU579434B2 (en) | 1988-11-24 |
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